Differentiation-specific increase in ALA-induced protoporphyrin IX accumulation in primary mouse keratinocytes.

A treatment regimen that takes advantage of the induction of intracellular porphyrins such as protoporphyrin IX (PPIX) by exposure to exogenous 5-amino-laevulinic acid (ALA) followed by localized exposure to visible light represents a promising new approach to photodynamic therapy (PDT). Acting upon the suggestion that the effectiveness of ALA-dependent PDT may depend upon the state of cellular differentiation, we investigated the effect of terminal differentiation upon ALA-induced synthesis of and the subsequent phototoxicity attributable to PPIX in primary mouse keratinocytes. Induction of keratinocyte differentiation augmented intracellular PPIX accumulation in cells treated with ALA. These elevated PPIX levels resulted in an enhanced lethal photodynamic sensitization of differentiated cells. The differentiation-dependent increase in cellular PPIX levels resulted from several factors including: (a) increased ALA uptake, (b) enhanced PPIX production and (c) decreased PPIX export into the culture media. Simultaneously, steady-state levels of coproporphyrinogen oxidase mRNA increased but aminolaevulinic acid dehydratase mRNA levels remained unchanged. From experiments using 12-o-tetradecanoylphorbol-13-acetate, transforming growth factor beta 1 and calcimycin we demonstrated that the increase in PPIX concentration in terminally differentiating keratinocytes is calcium- and differentiation specific. Stimulation of the haem synthetic capacity is seen in primary keratinocytes, but not in PAM 212 cells that fail to undergo differentiation. Interestingly, increased PPIX formation and elevated coproporphyrinogen oxidase mRNA levels are not limited to differentiating keratinocytes; these were also elevated in the C2C12 myoblast and the PC12 adrenal cell lines upon induction of differentiation. Overall, the therapeutic implications of these results are that the effectiveness of ALA-dependent PDT depends on the differentiation status of the cell and that this may enable selective targeting of several tissue types.     

Autoassociative MLP in Sleep Spindle Detection

Spindles are one of the most important short-lasting waveforms in sleep EEG. They are the hallmarks of the so-called Stage 2 sleep. Visual spindle scoring is a tedious workload, since there are often a thousand spindles in one all-night recording of some 8 hr. Automated methods for spindle detection typically use some form of fixed spindle amplitude threshold, which is poor with respect to inter-subject variability. In this work a spindle detection system allowing spindle detection without an amplitude threshold was developed. This system can be used for automatic decision making of whether or not a sleep spindle is present in the EEG at a certain point of time. An Autoassociative Multilayer Perceptron (A-MLP) network was employed for the decision making. A novel training procedure was developed to remove inconsistencies from the training data, which was found to improve the system performance significantly.     

Fludarabine in combination with alemtuzumab is effective and feasible in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: results of a phase II trial.

PURPOSE: To determine the efficacy and safety of a newly developed concomitant administration of fludarabine and alemtuzumab (FluCam) in patients with relapsed or refractory B-cell chronic lymphocytic leukemia (B-CLL). PATIENTS AND METHODS: A total of 36 patients were treated in this phase II study (median age, 61.47 years; mean number of prior chemotherapies, 2.6; Binet stage C, n = 28). After an initial dose escalation of alemtuzumab over 3 days, alemtuzumab 30 mg and fludarabine 30 mg/m2 were administered on 3 consecutive days. Treatment was repeated after 28 days for up to six cycles. Restaging (following National Cancer Institute criteria) was carried out after cycles 2 and 4 and 1 month after the end of treatment. RESULTS: The overall response rate was 83% (11 complete responses, 19 partial responses, one stable disease, and five progressive diseases). Two patients with progressive disease developed fungal pneumonias, and one patient died as a result of Escherichia coli sepsis. Two subclinical cytomegalovirus reactivations occurred. CONCLUSION: The new FluCam regimen is effective and feasible in patients with relapsed and refractory B-CLL.     

Heparin octasaccharides inhibit angiogenesis in vivo.

BACKGROUND: In previous experiments, we showed that heparin oligosaccharides inhibit the angiogenic cytokine fibroblast growth factor-2. Here, we present the first in vivo study of size-fractionated heparin oligosaccharides in four models of angiogenesis that are progressively less dependent on fibroblast growth factor-2. EXPERIMENTAL DESIGN: Heparin oligosaccharides were prepared using size-exclusion gel filtration chromatography and characterized through depolymerization and strong anion exchange high-performance liquid chromatography. Size-defined oligosaccharides (20 mg/kg/d) were given to mice bearing s.c. sponges that were injected with fibroblast growth factor-2 (100 ng/d). After 14 days, octasaccharides and decasaccharides reduced the microvessel density to levels below control. In a second experiment, HEC-FGF2 human endometrial cancer cells that overexpress fibroblast growth factor-2 were implanted in a hollow fiber placed s.c. in vivo. Oligosaccharides were given at 20 mg/kg/d for 2 weeks and the data again showed that octasaccharides significantly reduced microvessel density around the fiber (P = 0.03). In a more complex model, where angiogenesis was induced by a broad spectrum of growth factors, including vascular endothelial growth factor, we implanted H460 lung carcinoma cells in hollow fibers and treated the animals with oligosaccharides at 20 mg/kg/d over 3 weeks. Octasaccharides reduced the microvessel density to that of control. Preliminary investigation of 6-O-desulfated heparins showed that these also had antiangiogenic activity. RESULTS: Finally, we examined the inhibitory potential of hexasaccharides and octasaccharides given at 20 mg/kg/d and these inhibited the growth of H460 lung carcinoma in vivo. At clinically attainable concentrations, significant anticoagulation (activated partial thromboplastin time, anti-factor Xa, and anti-factor IIa) was not observed in vitro unless species containing > or =16 saccharide residues were investigated. CONCLUSIONS: Thus, our preclinical data show that heparin octasaccharides represent novel antiangiogenic compounds that can be given without the anticoagulant effects of low molecular weight heparin.     

Determination of the pericardial to serum myoglobin ratio for the early diagnosis of perioperative myocardial infarction after coronary artery bypass grafting.

Pericardial fluid reflect the composition of cardiac interstitium in myocardial ischemia. This study investigated the value of the pericardial and serum myoglobin (MG) measurements for the diagnosis of perioperative myocardial infarction (MI) after coronary artery bypass grafting (CABG). Postoperative arterial and pericardial blood samples were taken in 64 subjects undergoing elective CABG allocated to two groups according to the 12-lead electrocardiogram (ECG) abnormalities observed during the first postoperative 24h. Group 1=normal and nonspecific ECG abnormalities, and Group 2=perioperative Q-wave MI. The occurrence of perioperative MI was associated with a dramatic increase in both serum and pericardial cardiac troponin I (CTnI) and MG concentrations. Pericardial concentrations were higher than serum concentrations during the first postoperative 24h in all subject. However, pericardial/serum CTnI ratio in subjects in Group 2 was not statistically different from Group 1 at the time of admission to the intensive care unit (ICU) and did not significantly change at time intervals. On the other hand, more than two-fold increase in the pericardial/serum MG ratio was determined for all patients who experienced perioperative Q-wave MI with the lowest value as 2.75, whereas only 1 of 59 patients in group 1 had the ratio higher than 2 with the highest value as 2.15 at the time of admission to the ICU. In conclusion, determination of pericardial/serum MG ratio may be a useful tool for the early diagnosis of the perioperative MI after CABG.     

Women's empowerment and fertility preferences of married women: analysis of demographic and health survey’2016 in Timor-Leste

A recently independent state, Timor-Leste, is progressing towards socioeconomic development, prioritizing women empowerment while its increased fertility rate (4.1) could hinder the growth due to an uncontrolled population. Currently, limited evidence shows that indicators of women''s empowerment are associated with fertility preferences and rates. The objective of this study was to assess the association between women empowerment and fertility preferences of married women aged 15 to 49 years in Timor-Leste using nationally representative survey data. The study was conducted using the data of the latest Timor-Leste Demographic and Health Survey 2016. The study included 4040 rural residents and 1810 urban residents of Timor-Leste. Multinomial logistic regression has been performed to assess the strength of association between the exposures indicating women''s empowerment and outcome (fertility preference). After adjusting the selected covariates, the findings showed that exposures that indicate women empowerment in DHS, namely, the employment status of women, house and land ownership, ownership of the mobile phone, and independent bank account status, contraceptive use, and the attitude of women towards negotiating sexual relations are significantly associated with fertility preferences. The study shows higher the level of education, the less likely were the women to want more children, and unemployed women were with a higher number of children. Our study also found that the attitude of violence of spouses significantly influenced women''s reproductive choice. However, employment had no significant correlation with decision-making opportunities and contraceptive selection due to a lack of substantial data. Also, no meaningful data was available regarding decision-making and fertility preferences. Our findings suggest that women''s empowerment governs decision-making in fertility preferences, causing a decline in the fertility rate.     

一例47岁精神状态改变合并急性肾衰的病例分析

病例介绍患者,男,47岁,由于精神状态改变合并急性肾衰于6月初的一天早上10点送入我院急诊科。该患者在前一天晚上8点与家人共进晚餐时出现行为异常,餐后又开车外出。根据其妻子的描述,当晚回到家时,患者说话含糊不清并出现嗜睡。到晚9点出现呕吐并且昏睡。凌晨3点其妻子叫他无反应,遂拨打急诊中心电话,将患者送至当地医院急诊科。该患者最近没有发热、患病以及抑郁症状。曾患有肠易激综合征(服用了阿托品与地芬诺酯治疗)、慢性背部疼痛和焦虑,对青霉素过敏,没有个人或者家族重要疾病史。患者有吸烟和酗酒史,但近年无饮酒,其妻子确认其没有使…     

Effects of subchronic exposure to zinc nanoparticles on tissue accumulation,serum biochemistry,and histopathological changes in tilapia (Oreochromis niloticus)

Zinc nanoparticles (ZnNPs) are among the least investigated NPs and thus their toxicological effects are not known. In this study, tilapia (Oreochromis niloticus) were exposed to 1 and 10 mg/L suspensions of small size (SS, 40–60 nm) and large size (LS, 80–100 nm) ZnNPs for 14 days under semi‐static conditions. Total Zn levels in the intestine, liver, kidney, gill, muscle tissue, and brain were measured. Blood serum glucose (GLU), glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and lactate dehydrogenase (LDH) were examined to elucidate the physiological disturbances induced by ZnNPs. Organ pathologies were examined for the gills, liver, and kidney to identify injuries associated with exposure. Significant accumulation was observed in the order of intestine, liver, kidney, and gills. Zn levels exhibited time‐ and concentration‐dependent increase in the organs. Accumulation in kidney was also dependent on particle size; NPs SS‐ZnNPs were trapped more effectively than LS‐ZnNPs. No significant accumulation occurred in the brain (p > 0.05) while Zn levels in muscle tissue increased only marginally (p ≥ 0.05). Significant disturbances were noted in serum GOT and LDH (p < 0.05). The GPT levels fluctuated and were not statistically different from those of controls (p > 0.05). Histopathological tubular deformations and mononuclear cell infiltrations were observed in kidney sections. In addition, an increase in melano‐macrophage aggregation intensity was identified on the 7th day in treatments exposed to LS‐ZnNPs. Mononuclear cell infiltrations were identified in liver sections for all treatments. Both ZnNPs caused basal hyperplasia in gill sections. Fusions appeared in the gills after the 7th day in fish treated with 10 mg/L suspensions of SS‐ZnNPs. In addition, separations in the secondary lamella epithelia were observed. The results indicated that exposure to ZnNPs could lead to disturbances in blood biochemistry and cause histopathological injuries in the tissues of O. niloticus. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 1213–1225, 2017.